A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL.
A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL.
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DOI：
10.1021/acschembio.0c00348
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发表时间：
2020-07-17
影响因子：
4
通讯作者：
Nomura DK
中科院分区：
文献类型：
--
作者：
Tong B;Spradlin JN;Novaes LFT;Zhang E;Hu X;Moeller M;Brittain SM;McGregor LM;McKenna JM;Tallarico JA;Schirle M;Maimone TJ;Nomura DK
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Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific proteins in a proteasome-dependent manner. However, a major limitation of TPD is the lack of E3 ligase recruiters. Recently, we discovered the natural product nimbolide as a covalent recruiter for the E3 ligase RNF114. Here, we show the broader utility of nimbolide as an E3 ligase recruiter for TPD applications. We demonstrate that a PROTAC linking nimbolide to the kinase and BCR-ABL fusion oncogene inhibitor dasatinib, BT1, selectively degrades BCR-ABL over c-ABL in leukemia cancer cells, compared to previously reported cereblon or VHL-recruiting BCR-ABL degraders that show opposite selectivity or in some cases inactivity. Thus, we further establish nimbolide as an additional general E3 ligase recruiter for PROTACs, and demonstrate the importance of expanding upon the arsenal of E3 ligase recruiters, as such molecules confer differing selectivity for the degradation of neo-substrate proteins.
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影响因子：
11.2
作者：
Hines J;Lartigue S;Dong H;Qian Y;Crews CM
通讯作者：
Crews CM
影响因子：
14.8
作者：
Olson CM;Jiang B;Erb MA;Liang Y;Doctor ZM;Zhang Z;Zhang T;Kwiatkowski N;Boukhali M;Green JL;Haas W;Nomanbhoy T;Fischer ES;Young RA;Bradner JE;Winter GE;Gray NS
通讯作者：
Gray NS
DOI：
10.1126/science.aab1433
发表时间：
2015-06-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Winter GE;Buckley DL;Paulk J;Roberts JM;Souza A;Dhe-Paganon S;Bradner JE
通讯作者：
Bradner JE
影响因子：
5.7
作者：
Shibata N;Miyamoto N;Nagai K;Shimokawa K;Sameshima T;Ohoka N;Hattori T;Imaeda Y;Nara H;Cho N;Naito M
通讯作者：
Naito M
影响因子：
8.6
作者：
Zeng, Mei;Xiong, Yuan;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.